Stroma in breast development and disease

Abstract

It is increasingly apparent that normal and malignant breast tissues require complex local and systemic stromal interactions for development and progression. During development, mammary cell fate specification and differentiation require highly regulated contextual signals derived from the stroma. Likewise, during breast carcinoma development, the tissue stroma can provide tumor suppressing and tumor-promoting environments that serve to regulate neoplastic growth of the epithelium. This review focuses on the role of the stroma as a mediator of normal mammary development, as well as a critical regulator of malignant conversion and progression in breast cancer. Recognition of the important role of the stroma during the progression of breast cancers leads to the possibility of new targets for treatment of the initial breast cancer lesion as well as prevention of recurrence.

Figure 1. Stromal cells and the tumor microenvironment in the HIM model

(A) GFP-whole mount and H&E stains of humanized glands injected with GFP-lentivirus infected HMECs (top panel) or GFP + oncogene-lentivirus infected HMECs (bottom panel). Fibroblasts are present sparsely within the humanized area embedding the normal epithelial outgrowths (top panel) and as a dense stromal reaction surrounding tumor outgrowths. (B) GFP-labeled human immortalized fibroblasts used for humanizing the cleared mammary fat pads are present at 2 weeks post-humanizing (left) but are replaced by a strong recruitment of mouse-derived stromal cells (Right). Fluorescence in-situ hybridization for mouse Cot1 DNA (red) indicates that recruited stromal cells (S) are of mouse origin. Human tumor cells (T) are identified by staining for DAPI alone (blue). (C) (Left) Recruited stromal cells (S) include αSMA-positive (green) myofibroblast-like cells and F4/80-positive (red) macrophages. Human tumor cells (T) are labeled with DAPI alone (blue). (Right) Human tumor cells stained with human-specific Vimentin antibody (red).